A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers

Rinz, Caitlin J.; Lennon, Vanda A.; James, Fiona; Thoreson, James B.; Tsai, Kate L.; Starr-Moss, Alison N.; Humphries, Hammon D.; Guo, Ling; Palmer, Alan M.; Clark, Leigh Anne; Shelton, G. Diane

doi:10.1016/j.nmd.2015.09.005

Cited by 12 publications

(37 citation statements)

References 25 publications

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“…Congenital myasthenic syndromes have been reported in Smooth Fox Terriers, Springer Spaniels, Long-haired Miniature Dachshunds, Jack Russell Terriers, Labrador Retrievers, Golden Retrievers, and Old Danish Pointing dogs (Gammel Dansk Hønsehund) ( 1 , 2 , 5 – 9 ). There is a single report of two mongrel dogs with suspected CMS; however, confirmatory diagnostic testing was not performed ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

“…This finding supported skeletal muscle AChR deficiency consistent with a CMS. Histochemical and cytochemical staining of muscle cryosections (8 µm) was performed for localization of motor end-plates using the esterase reaction with serial sections stained for localization of AChRs using labeled α-bungarotoxin by immunofluorescence ( 2 ). Compared to archived control muscle, motor end-plates were identified but AChRs were undetectable (Figure 2 ) further supporting a diagnosis of CMS.…”

Section: Case Presentationmentioning

confidence: 99%

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Congenital Myasthenic Syndrome in a Mixed Breed Dog

et al. 2017

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A 6-month-old, male, intact mixed breed dog was presented for a 3-month history of progressive generalized weakness. Neurologic examination revealed non-ambulatory tetraparesis, weakness of the head and neck, and decreased withdrawal reflexes in all limbs consistent with a generalized neuromuscular disorder. Electromyography and motor nerve conduction velocity were normal. Repetitive nerve stimulation showed a decremental response of the compound muscle action potential with improvement upon intravenous administration of edrophonium chloride. The serum acetylcholine receptor (AChR) antibody titer was within reference range. Cerebrospinal fluid analysis was unremarkable. A presumptive diagnosis of post-synaptic congenital myasthenic syndrome (CMS) was made. Treatment with pyridostigmine bromide was initiated with titrated increases in dosage resulting in an incomplete improvement in clinical signs. The dog was euthanized 2 months after initiation of treatment due to poor quality of life. Immunostaining for localization of antibodies against end-plate proteins in muscle biopsies was negative. Immunofluorescence staining for AChRs in external intercostal muscle biopsies showed absence of AChRs and biochemical quantitation showed a markedly decreased concentration of AChRs with no detectable AChR-bound autoantibody which confirmed the diagnosis of a CMS. Evaluation for the CHRNE mutation previously identified as the causative mutation of CMS in Jack Russell Terriers was performed and was negative. This is the first reported confirmed case of CMS in a mixed breed dog and provides a review of typical clinical and diagnostic findings as well as treatment considerations.Keywords: congenital myasthenic syndrome, myasthenia gravis, dog, pyridostigmine bromide, mixed breed, CHRNE Case pReseNtatIoNA 6-month-old, male, intact mixed breed dog [6.54 kg (14.4 lb)] was referred with a 3-month history of progressive generalized weakness. The dog was adopted at approximately 3 months of age after having been found as a stray. At the time of adoption, the dog was perceived to be normal. About 1 week later, it was noted that the dog developed an abnormal, stiff gait after playing and would sometimes fall over. The dog was also having difficulty posturing to defecate. Despite empirical treatment with clindamycin (12.3 mg/kg, PO, BID) and steroids (unknown type or dose), the dog displayed progressive episodes of weakness and falling following activity that eventually progressed to non-ambulatory tetraparesis over the next several months. On presentation, physical examination revealed grade 3/6 left and right apical systolic murmurs. Echocardiogram revealed mitral valve dysplasia causing systolic anterior motion of the mitral valve with severe dynamic left ventricular outflow tract obstruction and mild mitral regurgitation. In addition, there was a mild dynamic right ventricular outflow tract obstruction. Atenolol (1 mg/kg, PO, BID) was initiated. On neurologic examination, the dog was non-ambulatory tetraparetic (lower motor neuron qu...

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Section: Discussionmentioning

confidence: 99%

Section: Case Presentationmentioning

confidence: 99%

Congenital Myasthenic Syndrome in a Mixed Breed Dog

et al. 2017

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“…For histochemical localization of motor end‐plates, serial cryosections (8 μm) were obtained from the external intercostal muscle of 1 affected GR collected at necropsy. In addition, archived frozen muscle of a previously diagnosed Jack Russell Terrier with CMS caused by end‐plate acetylcholine receptor (AChR) deficiency (neuromuscular disease control) and archived normal dog intercostal muscle (wild‐type control) were included. Sections from each dog were incubated with the esterase reaction for identification of presumptive motor end‐plates or Alexa Fluor 594 α‐bungarotoxin (1:1000, Molecular Probes) for localization of AChRs at the motor end‐plate according to published procedures .…”

Section: Methodsmentioning

confidence: 99%

“…In addition, archived frozen muscle of a previously diagnosed Jack Russell Terrier with CMS caused by end‐plate acetylcholine receptor (AChR) deficiency (neuromuscular disease control) and archived normal dog intercostal muscle (wild‐type control) were included. Sections from each dog were incubated with the esterase reaction for identification of presumptive motor end‐plates or Alexa Fluor 594 α‐bungarotoxin (1:1000, Molecular Probes) for localization of AChRs at the motor end‐plate according to published procedures . Serial sections were evaluated by light microscopy (esterase reaction) or fluorescent microscopy (red fluorescence) followed by localization of staining for comparison.…”

Section: Methodsmentioning

confidence: 99%

“…Although the first clinical report of congenital MG in dogs was published in 1974, only a few gene mutations causing CMS have been identified. These include a missense mutation in the gene encoding choline acetyltransferase in Danish Pointing dogs, a nonsynonymous mutation in the gene encoding the collagen‐like tail of the asymmetric acetylcholinesterase ( COLQ ) in Labrador Retrievers, and a deletion and nonsynonymous mutation in the gene encoding the epsilon subunit of the nicotinic acetylcholine receptor ( CHRNE) in Jack Russell Terriers and in Heideterriers, respectively. Congenital myasthenic syndromes also have been clinically described in Smooth Fox terriers and English Springer Spaniels, but mutations have not yet been described.…”

Section: Introductionmentioning

confidence: 99%

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Congenital myasthenic syndrome in Golden Retrievers is associated with a novelCOLQmutation

Tsai

Vernau

Winger

et al. 2019

Veterinary Internal Medicne

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Background: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog.Hypothesis/Objective: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies.Animals: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs.Methods: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database.

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Myasthenia gravis and congenital myasthenic syndromes in dogs and cats: A history and mini-review

Shelton

2016

Neuromuscular Disorders

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A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers

Cited by 12 publications

References 25 publications

Congenital Myasthenic Syndrome in a Mixed Breed Dog

Congenital Myasthenic Syndrome in a Mixed Breed Dog

Congenital myasthenic syndrome in Golden Retrievers is associated with a novelCOLQmutation

Myasthenia gravis and congenital myasthenic syndromes in dogs and cats: A history and mini-review

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